Tumor necrosis factor alpha (TNFα), a mononuclear cytokine, possesses various biological activities, such as killing cancer cells or inhibiting growth of cancer cells, enhancing the phagocytosis of neutrophilic granulocyte, and up-regulating the production of peroxide region. Interleukin-1 beta (IL-1β), a cytokine secreted by monocyte macrophages and dendritic cells, mediates immune and inflammatory responses. Nuclear factor-kappa B (NF-κB), a pro-inflammatory transcription factor, upregulates cytokines (e.g., TNFα and IL-1β) and thereby mediates the inflammatory response. Inducible nitric oxide synthase (iNOS) is induced by endotoxins or cytokines (e.g., TNFα and IL-1β). It catalyzes the production of nitric oxide, an important pleiotropic molecule, from L-arginine and oxygen.
TNFα, IL-1β, NF-κB, and iNOS all play critical roles in important physiological and pathological processes. A wide range of diseases, e.g., autoimmune disease, cancer, atherosclerosis, or diabetes, can be treated by modulating their expression or activity. See, e.g., Ogata H, Hibi T. et al Curr Pharm Des. 2003; 9(14): 1107-13; Taylor P C. et al Curr Pharm Des. 2003; 9(14): 1095-106; Fan C., et al. J. Mol. Med 1999, 77, 577-592; and Alcaraz et al., Current Pharmaceutical Design, 2002: 8, 215.